1. Field of the Invention
The present invention generally relates to treatments for inflammation. More specifically, the invention is directed to the use of tanshinones and tanshinone derivatives to inhibit inflammatory cytokine production.
2. Description of the Related Art
“Severe sepsis” is a syndrome defined by signs of organ dysfunction that include abnormalities in body temperature, heart rate, respiratory rate, and leukocyte counts. Despite recent advances in antibiotic therapy and intensive care, sepsis is still the most common cause of death in the intensive care units, claiming approximately 225,000 victims annually in the U.S. alone. The pathogenesis of sepsis is attributable, at least in part, to dys-regulated systemic inflammatory responses characterized by excessive accumulation of various proinflammatory mediators such as tumor necrosis factor (TNF) (Tracey et al. 1987), interleukin (IL)-1 (Dinarello and Thompson 1991), interferon (IFN)-γ (Heinzel 1990), nitric oxide (Dinapoli et al. 1996), and macrophage migration inhibitory factor (MIF) (Calandra et al. 2000; Hotchkiss and Karl 2003; Riedemann et al. 2003 b).
A ubiquitous protein, high mobility group box 1 (HMGB1), is released by activated macrophages/monocytes (Chen et al. 2004; Rendon-Mitchell et al. 2003; Tang et al. 2006; Wang et al. 1999), and functions as a late mediator of lethal endotoxemia and sepsis (Wang et al. 1999; Wang et al. 2004b; Wang et al. 2004c; Yang et al. 2004). Circulating HMGB1 levels are elevated in a delayed fashion (after 16-32 h) in endotoxemic and septic mice (Wang et al. 1999; Yang et al. 2004), and in patients with sepsis (Wang et al. 1999). Administration of recombinant HMGB1 to mice recapitulates many clinical signs of sepsis, including fever (O'Connor et al. 2003), derangement of intestinal barrier function (Sappington et al. 2002), tissue injury (Abraham et al. 2000), and multiple organ failure (Wang et al. 1999). Administration of anti-HMGB1 antibodies or inhibitors (e.g., ethyl pyruvate, nicotine, or stearoyl lysophosphatidylcholine) significantly protects mice against LPS-induced acute tissue injury (Abraham et al. 2000; Ueno et al. 2004), and lethal endotoxemia (Chen et al. 2005; Wang et al. 1999; Wang et al. 2004b; Wang et al. 2004a). Notably, these anti-HMGB1 reagents are capable of rescuing mice from lethal experimental sepsis even when the first doses are given 24 h after the onset of sepsis (Qin et al. 2006; Ulloa et al. 2002; Wang et al. 2004b; Yang et al. 2004), indicating a wider window for HMGB1-targeted therapeutic strategies. Therefore, agents proven clinically safe, and yet still capable of attenuating HMGB1 release may hold potential in the prevention and treatment of inflammatory diseases.
Throughout human history, herbal medicine has formed the basis of folk remedies for various inflammatory ailments. The use of willow bark extract to reduce pain and fever was documented by a Greek physician (Hippocrates) in the 5th century BC, and the subsequent discovery of salicylic acid as its pain/fever-relief active component gave rise to the first synthetic non-steroidal anti-inflammatory drug (NSAID)—aspirin, and the birth of the pharmaceutical industry. Among thousands of Chinese medicinal herbs, only a few have been entitled “Shen” [e.g., Ren Shen (ginsen), Dan Shen (Salvia miltiorrhiza)]. Danshen refers to a medicinal herb (termed “shen”) containing substance of premier medicinal value (termed “Dan”, cinnabar), and has been widely used in China for patients with cardiovascular disorders (Ji et al. 2000). Its beneficial effects are attributable to several red pigments including tanshinone I, II, IV, and cryptotanshinone (Wu et al. 1993; Yagi et al. 1994), which exhibit various anti-inflammatory properties (Jang et al. 2003; Kang et al. 2000; Kim et al. 2002).
Several lines of evidence suggest some anti-inflammatory activities for a number of Danshen components (such as tanshinone I, II, and IV) (Jang et al. 2003; Kang et al. 2000; Kim et al. 2002; Li and Tang 1991; Shilin et al. 1987). Therefore, there is a need for further characterization of the effect of these compounds, or derivatives thereof, on inflammation and the release of mediators of inflammation, particularly the “late” inflammatory mediators. The present invention addresses that need.